Search

Background: Glucose metabolism and insulin signaling alterations play an important role in Alzheimer’s disease (AD) pathogenesis. Researchers have extensively attempted to characterize the exact pathophysiological mechanisms in the cerebrospinal fluid (CSF), as evidence concerning this fluid biomarkers is expected to enhance AD diagnosis’ specificity and accuracy and serve as an early disease detection tool. There is controversy about insulin levels in the CSF relationship with mild cognitive impairment (MCI) and AD. Objective: This systematic review provides an overview of the state-of-the-art knowledge about insulin-related CSF biomarkers in AD and MCI. Methods: We performed a qualitative systematic literature review of reported data of CSF glucose, insulin, or insulin-related molecules in humans with AD or MCI, consulting the electronic databases Medline, Scopus, Web of Science, Cochrane, and BASE until May 2022. Results: We selected 19 studies, 10 of them reporting data on CSF insulin and 8 on insulin-related molecules like growth factors or their binding proteins. They predominantly found decreased levels of CSF insulin and increased levels of CSF insulin-related growth factors and their binding proteins. Conclusion: Due to the studies’ protocols and results heterogeneity, we recommend a larger database of clinical trials with similar characteristics for a better understanding of this relationship.

This study aimed to identify inflammatory factors and soluble cytokines that act as biomarkers in the diagnosis and prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We performed a nested prospective observational case–control study of patients with RA-ILD matched by sex, age, and time since the diagnosis of RA. All participants underwent pulmonary function testing and high-resolution computed tomography. ILD was defined according to the criteria of the American Thoracic Society/European Respiratory Society; the progression of lung disease was defined as the worsening of FVC > 10% or DLCO > 15%. Inflammation-related variables included the inflammatory activity measured using the DAS28-ESR and a multiplex cytokine assay. Two Cox regression models were run to identify factors associated with ILD and the progression of ILD. The study population comprised 70 patients: 35 patients with RA-ILD (cases) and 35 RA patients without ILD (controls). A greater percentage of cases had higher DAS28-ESR (p = 0.032) and HAQ values (p = 0.003). The variables associated with RA-ILD in the Cox regression analysis were disease activity (DAS28) (HR [95% CI], 2.47 [1.17–5.22]; p = 0.017) and high levels of ACPA (HR [95% CI], 2.90 [1.24–6.78]; p = 0.014), IL-18 in pg/mL (HR [95% CI], 1.06 [1.00–1.12]; p = 0.044), MCP-1/CCL2 in pg/mL (HR [95% CI], 1.03 [1.00–1.06]; p = 0.049), and SDF-1 in pg/mL (HR [95% CI], 1.00 [1.00–1.00]; p = 0.010). The only variable associated with the progression of ILD was IL-18 in pg/mL (HR [95% CI], 1.25 [1.07–1.46]; p = 0.004). Our data support that the inflammatory activity was higher in patients with RA-ILD than RA patients without ILD. Some cytokines were associated with both diagnosis and poorer prognosis in patients with RA-ILD.

Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP). Lansoprazole is a partial inhibitor of TNAP. The aim was to investigate whether lansoprazole increases plasma PPi levels in subjects with PXE. We conducted a 2 × 2 randomized, double-blind, placebo-controlled crossover trial in patients with PXE. Patients were allocated 30 mg/day of lansoprazole or a placebo in two sequences of 8 weeks. The primary outcome was the differences in plasma PPi levels between the placebo and lansoprazole phases. 29 patients were included in the study. There were eight drop-outs due to the pandemic lockdown after the first visit and one due to gastric intolerance, so twenty patients completed the trial. A generalized linear mixed model was used to evaluate the effect of lansoprazole. Overall, lansoprazole increased plasma PPi levels from 0.34 ± 0.10 µM to 0.41 ± 0.16 µM (p = 0.0302), with no statistically significant changes in TNAP activity. There were no important adverse events. 30 mg/day of lansoprazole was able to significantly increase plasma PPi in patients with PXE; despite this, the study should be replicated with a large number of participants in a multicenter trial, with a clinical end point as the primary outcome.

Introduction Pathogenic variants in lipoprotein lipase (LPL) and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) have been described in patients with severe hypertriglyceridaemia. We aimed to optimise high resolution melting (HRM) assays to detect the presence of functional variants in these genes. Methods One hundred and sixteen patients with severe hypertriglyceridaemia were studied. HRM assays were optimised to scan exons and splice junctions in LPL and GPIHBP1. Sanger sequencing was the reference method. Next-generation-sequencing (NGS) was performed in five patients, including one with Familial Chylomicronemia syndrome (FCS). Results We identified 15 different variants in LPL and 6 in GPIHBP1. The variants revealed with NGS were also detected with HRM, including a rare premature stop codon in LPL (p.Trp421*) and two LPL pathogenic variants in the patient with FCS (p.His80Arg + p.Gly215Glu). Having multiple functional variant alleles was associated with pancreatitis onset at younger ages and higher baseline triglycerides. Conclusions Our HRM assays detected the presence of functional gene variants that were confirmed with Sanger and NGS sequencing. The presence of multiple functional variant alleles was associated with differences in the clinical profile. Therefore, these assays represent a reliable, cost-effective tool that can be used to complement the NGS approach for gene scanning.

ObjectivesTo describe the prevalence of insulin resistance (IR) in patients with established rheumatoid arthritis (RA) and to analyse the contribution of cumulative inflammatory burden and other factors to its development.DesignObservational cross-sectional study.ParticipantsPatients with RA and controls matched for age, sex and Body Mass Index. We excluded patients with diabetes.SettingsPatients from an RA inception cohort at Hospital Regional Universitario de Málaga, Spain, were recruited between September 2016 and May 2018.Primary and secondary outcome measuresIR was evaluated using the homeostasis model assessment for IR and beta-cell function and the quantitative insulin sensitivity check index. Other variables included the cumulative 28-Joint Disease Activity Score (DAS28) with C reactive protein (CRP) body composition and cytokines. Two logistic regression models were constructed to identify factors associated with IR in patients with RA.ResultsEighty-nine patients with RA and 80 controls were included. The prevalence of IR was similar in both cases and controls. Inflammatory activity was controlled appropriately in patients during follow-up (mean DAS28 3.1 (0.8)). The presence of IR in patients with RA was associated with obesity (OR 6.01, 95% CI 1.9 to 8.7), higher cumulative DAS28-CRP values during follow-up (OR 2.8, 95% CI 1.3 to 6.0), and higher interleukin-1β levels (OR 1.6, 95% CI 1.1 to 2.4). The second model showed that the risk of IR increased by 10% for each kilogram of excess body fat.ConclusionIn patients with well-controlled, established RA, IR is associated mainly with poorer control of inflammation from diagnosis and with obesity, specifically total fat mass.

Background The aim of this study is to confirm the diagnostic performance of the Chylomicron to very low-density lipoproteins triglycerides (CM/VLDL-TG) ratio, the triglycerides to cholesterol ratio (TG/TC) and a dichotomic rule including the tryglycerides to apolipoprotein B (TG/APOB) ratio for the presence of Type I hyperlipoproteinemia (HPLI) in patients with severe hypertriglyceridemia (sHTG) that were at high risk for familial chylomicronemia syndrome (FCS). Methods Two cohorts (derivation and validation) of patients with sHTG were included in the study. Anthropometric, clinical, biochemical and genetic data were obtained. The CM/VLDL-TG, TG/TC and TG/APOB ratios were calculated. Finally, a diagnostic performance study was developed to establish sensitivity, specificity and cut-offs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort. Results Patients with FCS in both cohorts showed an earlier presence in pancreatitis, greater number of acute pancreatitis episodes and lower BMI. FCS patients also showed higher ratios of CM/VLDL-TG, TG/TC and TG/APOB ratios, whereas their HDL-C, LDL-C and APOB levels were lower than in non-FCS patients. Sensitivity and agreement were low for both the TG/TC and TG/APOB ratios, although predictive values were good. The CM/VLDL-TG ratio showed greatest sensitivity, specificity, agreement and predictive values for cut-off of 3.8 and 4.5. Conclusions Our results suggest that in subjects at high risk of FCS a total serum TG/TC ratio or TG/APOB ratio are feasible to initially screen for HLPI; however, a CM/VLDL-TG ratio ≥4.5 is a better diagnostic criterion for HPLI.

Objective: To describe postprandial lipemia in patients with rheumatoid arthritis (RA) and to analyze its association with subclinical atherosclerosis measured as carotid intima-media thickness (cIMT). Methods: We performed an observational study of 40 patients with RA and 40 sex and age-matched controls. Patients with dyslipidemia were excluded. Pathologically increased cIMT was defined as a carotid thickness greater than the 90th percentile (&gt, p90) for age and sex. Fasting and postprandial plasma lipids, cholesterol, triglycerides, apolipoprotein B48 (ApoB48), and total ApoB were evaluated. The other variables included were clinical and laboratory values, Framingham score, and the 28-joint Disease Activity Score (DAS28). Two multivariate models were constructed to identify factors associated with pathologic cIMT in patients with RA. Results: Fasting lipid values were similar in patients with RA and controls, although those of postprandial ApoB48 were higher (median (IQR), 14.4 (10.8&ndash, 12.1) vs. 12.1 (2.3&ndash, 9,8), p = 0.042). Pathologic cIMT was recorded in 10 patients with RA (25%) and nine controls (22.5%). In patients with RA, pathologic cIMT was associated with postprandial ApoB48 (OR (95% CI), 1.15 (1.0&ndash, 1.3)) and total ApoB (OR [95% CI], 1.12 [1.1&ndash, 1.2]). The second model revealed a mean increase of 0.256 mm for cIMT in patients with elevated anticitrullinated protein antibodies (ACPAs). Conclusion: Postprandial ApoB48 levels in patients with RA are higher than in controls. Postprandial ApoB48 and total ApoB levels and markers of severity, such as ACPAs, are associated with pathologic cIMT in patients with RA. Our findings could indicate that these atherogenic particles have a negative effect on the endothelium.

Cardiovascular disease risk is increased in survivors of testicular cancer because of exposure to treatment (chemotherapy and radiotherapy), as well as modification in lifestyle. Our aim was to assess the presence of subclinical arteriosclerosis in survivors of testicular cancer in comparison with a control group. This was a cross-sectional, observational, case&ndash, control study including 50 survivors of Germ Cell Tumor (GCT) (14 years of follow-up) and 53 age-matched controls with no cancer. We registered clinical data, cardiovascular risk factors, physical and Mediterranean questionnaires, intima-media thickness and plaque at carotid and femoral arteries by ultrasound, calcium score at the abdominal aorta, and liver steatosis by computed tomography, and applied analytical tests to quantify metabolic risk factors and inflammation markers. Patients showed a trend toward greater intima-media thickness (IMT) and plaques than controls, as well as a higher calcium score in the abdominal aorta. Remarkably, patients had higher waist circumference, insulin resistance (HOMA-IR), and liver steatosis, but lower physical activity and high-density lipoprotein (HDL) cholesterol than controls (all p &lt, 0.05). In multivariate analyses, only common vascular risk factors were associated with subclinical arteriosclerosis. As a conclusion, in our study, a higher rate of subclinical arteriosclerosis in testicular cancer survivors was associated with classical metabolic risk factors and lifestyle, but not with exposure to chemotherapy.

ObjectivesTo study how patient groups that accept pharmaceutical industry money perceive and manage the risk of undue influence from their sponsors.DesignEmpirical ethics approach using a qualitative interview study.SettingThe Australian patient group sector.Participants27 participants from 23 patient groups, purposively recruited for diversity of group characteristics (degree of pharmaceutical industry funding, health focus, location) and participant role (staff, board members).AnalysisInterview data were transcribed and read repeatedly to identify concepts and patterns in the data. These were grouped into conceptual categories that described and explained the findings. We used an inductive analytical approach to identify important themes and concepts in the data.ResultsParticipants in this study described how the patient group sector receives pressure from pharmaceutical company funders to act in ways that prioritise company interests. Groups worked to try and protect their credibility and ability to act in ways of their own choosing using practical rules or ‘lines in the sand’ about industry funding activities. They were grouped around the dominant topics of: sponsor exclusivity, brand marketing, agenda setting, advocacy and content of group activities. Lines in the sand were largely experience-driven and ethically informed; they varied between groups. There was also variable transparency among groups about financial interactions with pharmaceutical companies.ConclusionsIt is important to know about patient group practices around pharmaceutical industry funders as this allows public scrutiny about the adequacy of such practices. Inadequate strategies may mean that funders can influence patient groups activities in ways that do not necessarily prioritise the interests of members. We found that groups differed in their approach, with little independent external guidance to inform responses to commonly encountered types of influence. Inadequate transparency limits the ability of the public to make informed assessments about the risk of bias over the activities of groups that accept industry funding.

ObjectivesFormative peer assessment focuses on learning and development of the student learning process. This implies that students are taking responsibility for assessing the work of their peers by giving and receiving feedback to each other. The aim was to compile research about formative peer assessment presented in higher healthcare education, focusing on the rationale, the interventions, the experiences of students and teachers and the outcomes of formative assessment interventions.DesignA scoping review.Data sourcesSearches were conducted until May 2019 in PubMed, Cumulative Index to Nursing and Allied Health Literature, Education Research Complete and Education Research Centre. Grey literature was searched in Library Search, Google Scholar and Science Direct.Eligibility criteriaStudies addressing formative peer assessment in higher education, focusing on medicine, nursing, midwifery, dentistry, physical or occupational therapy and radiology published in peer-reviewed articles or in grey literature.Data extractions and synthesisOut of 1452 studies, 37 met the inclusion criteria and were critically appraised using relevant Critical Appraisal Skills Programme, Joanna Briggs Institute and Mixed Methods Appraisal Tool tools. The pertinent data were analysed using thematic analysis.ResultThe critical appraisal resulted in 18 included studies with high and moderate quality. The rationale for using formative peer assessment relates to giving and receiving constructive feedback as a means to promote learning. The experience and outcome of formative peer assessment interventions from the perspective of students and teachers are presented within three themes: (1) organisation and structure of the formative peer assessment activities, (2) personal attributes and consequences for oneself and relationships and (3) experience and outcome of feedback and learning.ConclusionHealthcare education must consider preparing and introducing students to collaborative learning, and thus develop well-designed learning activities aligned with the learning outcomes. Since peer collaboration seems to affect students’ and teachers’ experiences of formative peer assessment, empirical investigations exploring collaboration between students are of utmost importance.

The role of renal excretion of Pi in relation to vascular calcification (VC) in patients in the early stages of chronic kidney disease (CKD) is controversial. Thus, we determine the relation between fractional excretion of phosphorus (FEP) and VC, measured using two methods in a cross-sectional study of patients with stage 3 CKD. We recorded demographic data, anthropometry, comorbidities and active treatment. We measured 24-hour urine FEP and, in serum, measured fibroblast growth factor 23 (FGF23), α-Klotho, intact parathyroid hormone (iPTH), calcium and phosphorus. VC was measured by lateral abdominal radiography (Kauppila index (KI)) and CT of the abdominal aorta (measured in Agatston units). In 57% of subjects, abnormal VC was present when measured using CT, and in only 17% using lateral abdominal radiography. Factors associated with VC using CT were age, cardiovascular risk factors, vascular comorbidity, microalbuminuria and levels of FGF23, phosphorus and calcium x phosphorus product (CaxP); although only age (OR 1.25, 95% CI 1.11 to 1.41), smoking (OR 21.2, CI 4.4 to 100) and CaxP (OR 1.21, CI 1.06 to 1.37) maintained the association in a multivariate analysis. By contrast, only age (OR 1.35, 95% CI 1.07 to 1.74), CaxP (OR 1.14, CI 1.13 to 1.92) and FEP (OR 1.07,95% CI 1004 to 1.14) were associated with abnormal VC in the lateral abdominal radiography. In conclusion, in patients with stage 3 CKD, the detection of VC by abdominal CT is more sensitive than conventional X-rays. Moreover, CaxP is associated with cardiovascular risk factors and vascular comorbidity; quantification of FEPi in these patients provides additional clinical information in advanced VC detected by KI.

It is not known whether COPD exacerbations contribute to an increased vascular risk already associated with the disease. For this reason, we prospectively evaluated 127 patients referred for a monographic COPD consultation. We classify as exacerbators those who had experienced two or more moderate exacerbations in the previous year, or who had had a hospital admission. All underwent a blood analysis, respiratory function tests, global cardiovascular and coronary risk estimates (with four of the most frequently used scores, and the Chronic Obstructive Pulmonary Disease Coronaropathy Risk (COPDCoRi) score, respectively); and an EcoDoppler to measure carotid intima-media thickness and the ankle-brachial index. Finally, we included 50 patients with exacerbator phenotypes and 57 with non-exacerbator phenotypes, ranging from 63 ± 7 years old, 74% of whom were male. The exacerbator phenotype increased the risk of carotid intima-media thickness above the 75th percentile range by a factor of almost three, independently of the severity of COPD and global cardiovascular risk. The association between the exacerbator phenotype and high c-IMT was more evident in patients under 65. In conclusion, the presence of subclinical atherosclerosis is independently associated with the exacerbator phenotype, with more pronounced differences in younger patient; which suggests that we should intensify control of vascular risk factors in these groups of patients.

Background Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex. Objective This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry. Methods Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5). Results Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326_327insC; p.Tyr110Leufs*158). Conclusion We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS.

BACKGROUND Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis. METHODS Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross-sectional study. Carotid intima-media thickness (cIMT) was measured as a surrogate for vascular damage. RESULTS In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 ± 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 ± 5.16 and 5.22 ± 2.46, P

Background/Objective: The aim was to assess the neuropsychological performance of a group of middle-aged patients with well-controlled type 2 diabetes mellitus (T2DM) and to examine whether the neuropsychological deficits correlate with structural and functional brain alterations. Methods: We compared 25 subjects with T2DM aged 45–65 years with 25 control participants matched for age, gender, and educational level. The neuropsychological battery was designed to examine executive functions, attention, information processing speed, and verbal memory. Severity of depression was assessed using the Hamilton Depression Rating Scale and cardiovascular risk factors were assessed using the Framingham Cardiovascular Risk Profile Score. The presence of at least one APOE4 allele was determined. Reduced gray matter density was analyzed using voxel-based morphometry and brain glucose metabolic changes were assessed by 18 FDG-PET. Results: T2DM subjects had significantly lower scores than subjects without T2DM in the Trail-making Test B (p < 0.004), Color-Word Stroop test (p < 0.005), Semantic Fluency (p < 0.006), Digit-Symbol modalities test (p < 0.02), Text Recall from the Wechsler Memory Scale (p < 0.0001), Rey-Osterrieth Complex Figure-copy (p < 0.004), and delayed reproduction (p < 0.03). Worse executive functions and memory functioning correlated predominantly with less gray matter density and reduced glucose metabolism in the orbital and prefrontal cortex, temporal (middle gyrus, parahippocampus and uncus), and cerebellum regions (p < 0.001). Conclusions: T2DM subjects presented cognitive dysfunctions compared with controls. Clinical-neuroimaging correlations corresponded to brain changes (reduced gray matter density and glucose metabolism) mainly in fronto-temporal areas.

OBJECTIVES To determine lipid serum levels, lipoproteins and other markers related to nephropathy and peripheral arterial disease (PAD) in a type 2 diabetes population stratified according to their level of renal dysfunction. METHODS A cross-sectional study was conducted on 72 type 2 diabetic patients followed-up in outpatient clinics. Patients were divided into 4 groups according to their estimated glomerular filtration rate (eGFR, mL/min) and albumin/creatinine ratio (ACR, mg/g) (eGFR > 60 and ACR 60 and ACR > 30 [n = 12], eGFR30-60 [n = 23] and eGFR < 30 [n = 14]). Clinical and anthropometric characteristic of all patients were recorded. Fasting lipids and apolipoproteins, as well as renal and hematology parameters were measured. Finally, a multivariate Wald stepwise logistic regression statistic analysis was performed to determine variables independently associated with the presence of renal dysfunction. RESULTS The univariate statistical analysis showed that the higher renal dysfunction, the higher the prevalence of hypertension, smoking habit and triglycerides levels, and the lower hemoglobin levels (P < .05). The multivariate statistical analysis showed that only triglycerides levels (OR: 1.019, 95% CI: 1.004-1.034) and hemoglobin levels (OR: 0.516 95% CI: 0.292-0.914) were independently associated to the presence of renal dysfunction (eGFR < 60 mL/min.). The further inclusion of the presence of PAD in the statistical model did not modify those associations. CONCLUSION The results confirm the relationship between triglycerides levels and diabetic nephropathy, independently of the presence of PAD.

Background: Inorganic pyrophosphate (PPi) plays a major role inhibiting dystrophic calcification. The aim was to analyze levels of PPi in patients having pseudoxanthoma elasticum (PXE), and controls as well as the enzymes who regulate the PPi plasma concentration. Methods: We collected fasting blood samples from PXE patients and age- and sex-matched controls in ethylenediamine tetraacetic acid (EDTA) and citrate-theophylline-adenosine-dipyridamole (CTAD) containing tubes. We measured PPi, ENPP1 mass and activity, alkaline phosphatase (AP) and tissue non-specific alkaline phosphatase (TNAP), CD73 and Human Platelet Factor-4 (CXCL4). Results: PPi in EDTA and CTAD samples were lower in PXE subjects than in controls (1.11±0.26 vs. 1.43±0.41 µM/L and 0.35±0.15 vs. 0.61±0.18 µM/L respectively, P

Eur J Clin Invest 2012; 42 (7): 702–708 Abstract Background Postprandial accumulation of atherogenic remnants has been described in patients with type 2 diabetes mellitus (T2DM), familial combined hyperlipidaemia (FCH), familial hypercholesterolaemia (FH) and coronary artery disease (CAD). Scarce data are available on fasting plasma apolipoprotein (apo) B48 levels in relation to these conditions and atherosclerosis. Design Treated patients with FCH (18), FH (20), T2DM (26), CAD (65), T2DM with CAD (T2DM/CAD) (28) and 33 healthy controls were included. Intima-media thickness (IMT) measurements were carried out to investigate subclinical atherosclerosis. Results LDL-C and total apoB were lowest in patients with T2DM/CAD owing to the more frequent use of lipid-lowering medication. Fasting plasma apoB48 was elevated in patients with FCH (11·38 ± 1·50 mg/L) and T2DM/CAD (9·65 ± 1·14 mg/L) compared with the other groups (anova, P

Resumen Introduccion Los trigliceridos se consideran un factor independiente de riesgo vascular. La influencia, por separado, de polimorfismos en genes como APOE, APOA5, LPL, LIPC y CETP sobre dichos niveles esta descrita, por lo que resulta de interes su analisis conjunto y el estudio de interacciones con factores ambientales. Metodos Se han genotipado en 1.825 sujetos (80% varones, edad media 36 anos) procedentes del estudio ICARIA, el polimorfismo de APOE , 2 variantes de APOA5 (S19W y -1131 T/C), 5 de LPL (D9N, N291S, PvuII, HindIII y S447X), 1 de LIPC (-250G/A) y 1 de CETP (TaqIβ) mediante PCR-restriccion y ensayos TaqMan. El efecto conjunto de las variantes se ha analizado mediante regresion lineal con la variable trigliceridos transformada logaritmicamente y corrigiendo por covariables. Las interacciones se han explorado mediante contrastes multiples. Resultados El alelo ɛ4 de APOE , los polimorfismos de APOA5 S19W y -1131T/C y las variantes de LPL , D9N y N291S mostraron un efecto elevador de trigliceridos significativo e independiente. Los polimorfismos HindIII y S447X de LPL se asociaron significativamente con una reduccion de los niveles de TG. Las variantes PvuII (LPL), -250G/A (LIPC) y TaqIβ (CETP) no mostraron asociaciones significativas. Se encontro una tendencia estadistica (p=0,048) para la interaccion entre obesidad abdominal (perimetro de cintura >102 cm en hombres; >88 cm en mujeres) y el alelo APOE -ɛ4. Conclusiones Nuestro trabajo muestra la influencia del alelo ɛ4 de APOE y de las variantes S19W y -1131T/C de APOA5 y D9N, N291S, HindIII y S447X de LPL sobre los niveles de trigliceridos y sugiere un efecto modulador de la obesidad abdominal sobre el alelo ɛ4.

Background Postprandial hyperlipidemia is a common feature in type 2 diabetes; our aim was to investigate whether there is an association between subclinical peripheral arterial disease (PAD) and the levels of apolipoprotein B48, as a specific marker for postprandial lipidemia. Methods We enrolled 101 patients with type 2 diabetes and 73 controls free from clinical cardiovascular disease. Main outcome measures were the presence of subclinical PAD, assessed by the ankle-brachial index, and the intestinal particles measured as the concentration of apolipoprotein B48 at fasting and 4 h after a mixed breakfast. Results No control had subclinical PAD. Of the 101 diabetic patients, 21 had subclinical PAD. The levels of apo B48, both fasting and postprandial, were only significantly raised in the diabetic patients who had PAD. The diabetic patients without vascular disease had similar concentrations of triglycerides and apo B48 to the controls. In binary logistic regression analyses, only smoking and postprandial B48 levels, in addition to diabetes, were independently associated with PAD. On the other hand, PAD but not diabetes was associated with the fasting and postprandial levels of apo B48. Conclusion Our study suggests that apolipoprotein B48 levels might be a marker of occult PAD in patients suffering from type 2 diabetes mellitus. Accordingly, subclinical PAD should be taken into account in studies on postprandial lipidemia involving patients with diabetes.

Introduccion En el presente trabajo, hemos evaluado las diferencias en la respuesta posprandial, incluidos en esta los valores de la apolipoproteina (apo) B-48 y el perfil lipidico, entre varones y mujeres, en una poblacion de pacientes con diabetes mellitus tipo 2 (DM2). Tambien se analizo la relacion entre la apo B-48 y determinadas variables antropometricas, glucidicas y lipidicas implicadas en la aparicion y desarrollo de la enfermedad diabetica. Pacientes y metodos Se recogieron los datos antropometricos y clinicos de 50 pacientes con DM2 y se tomaron muestras de 12 h de ayunas y 4 h despues de un desayuno mixto. A las muestras de plasma, en ayunas de 12 h, por centrifugacion, se les cuantifico hemoglobina glucosilada, indice HOMA-IR, fenotipo de las lipoproteinas de baja densidad, apo A-1, apo B-100, perfil lipidico y apo B-48. Se cuantifico tambien el perfil lipidico y los valores de apo B-48 de las muestras posprandiales. Resultados Ambos sexos difirieron unicamente en los valores de colesterol unido a lipoproteinas de alta densidad (p Conclusiones Comprobamos que los trigliceridos y la apo B-48, variables que presentan un fuerte incremento posprandial, especialmente en la apo B-48, son similares en ambos sexos y que el principal parametro asociado con los valores de apo B-48 en estos individuos son los valores de trigliceridos en ayunas y posprandiales.

This study aimed to investigate the association between a polymorphism in the hepatic lipase (LIPC) gene promoter and the presence of peripheral arterial disease (PAD) in persons with type 2 diabetes.We evaluated 120 type 2 diabetics and identified those with PAD according to the ankle-arm index. The G-250A polymorphisms in the promoter of the LIPC gene were studied by PCR restriction. A logistic regression analysis was performed to determine the association between the rare allele and PAD.The prevalence of PAD was 19%. The frequency of the -250A allele was 0.211 in the group without PAD and 0.395 in the group with PAD (P.05). Carriers of the -250A allele differed only in the ankle-arm index (0.92+/-0.12 for carriers vs. 1.00+/-0.12 for noncarriers, P.05), with the difference remaining significant after adjustment for covariates (age; sex; waist-to-hip ratio; body mass index; duration of diabetes; smoking; hypertension; glycated hemoglobin; triglycerides; HDL cholesterol; LDL cholesterol; small, dense LDL cholesterol). Only smoking [odds ratio (OR)=6.93, 95% confidence interval (CI)=2.12-22.69, P=.001] and the -250A allele (OR=2.89, 95% CI=1.07-7.84, P=.036) were significantly associated with vascular disease in the logistic regression analysis.Patients with type 2 diabetes who are carriers of the rare -250A allele in the promoter of the hepatic lipase gene are susceptible to PAD.

Introduccion La enfermedad arterial periferica (EAP) puede considerarse un predictor de mortalidad cardiovascular. Como otras enfermedades provocadas por la arteriosclerosis aparece como consecuencia de la interaccion entre numerosos factores ambientales y geneticos. A pesar del impacto en la salud y la prevalencia de la EAP, especialmente elevada en diabeticos, se conoce poco acerca de las variantes geneticas que confieren susceptibilidad a esta enfermedad. Objetivo Estudiar la asociacion entre el polimorfismo – 250G/A del promotor del gen de lipasa hepatica (LIPC) y la presencia de enfermedad arterial periferica en individuos con diabetes tipo 2. Pacientes y metodos Se han estudiado 78 personas sin diabetes ni EAP y 138 pacientes diabeticos tipo 2 en los que se ha diagnosticado la presencia de EAP mediante el indice tobillo-brazo. El polimorfismo – 250G/A se ha analizado mediante PCR y restriccion. Para demostrar la asociacion entre la presencia del alelo - 250A y la EAP se ha realizado un analisis de regresion logistica. Resultados Segun el analisis de regresion logistica por pasos hacia delante, la presencia del alelo – 250A ( odds ratio: 2,80; intervalo de confianza del 95%, 1,06-7,40; p 1c ), indice de masa corporal, trigliceridos, colesterol unido a lipoproteinas de alta densidad y colesterol unido a lipoproteinas de baja densidad en el modelo. La prevalencia de EAP en los portadores del alelo fue del 31,3% y solo del 13,3% en no portadores (p Conclusion Nuestro estudio muestra que el alelo menos frecuente del polimorfismo – 250G/A del promotor de LIPC se asocia independientemente con la presencia de EAP en pacientes diabeticos tipo 2.

To study the association between adiponectin plasma levels, and gray matter brain volume and cerebral glucose metabolism in a group of type 2 diabetes patients.We studied 25 type 2 diabetes patients and 25 age- and gender-matched healthy control participants. Biochemical analysis and structural cerebral magnetic resonance imaging, including voxel-based morphometry and (18)-fluorodeoxyglucose positron emission tomography, were performed. The gray matter volumes and metabolism changes were analyzed using statistical parametric mapping (SPM8).Lower levels of adiponectin correlated with a lower gray matter volume in temporal regions and with reduced cerebral glucose metabolism in temporal regions (p0.001), adjusted for age, gender, education, and the presence of at least one epsilon 4 allele for the apolipoprotein E (APOEε4 genotype).Positive correlations between adiponectin plasma levels and both gray matter volume and cerebral glucose metabolism were found, predominantly in temporal regions, as in Alzheimer's disease. Adiponectin might be a biomarker for the cognitive decline associated with type 2 diabetic patients.

Background and aims The postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers. Methods Leukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h). Results Fasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 ± 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 ± 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression. Conclusion This study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia.

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) has been demonstrated to be essential for the in vivo function of lipoprotein lipase (LPL), the major triglyceride (TG)-hydrolyzing enzyme involved in the intravascular lipolysis of TG-rich lipoproteins. Recently, loss-of-function mutations of GPIHBP1 have been reported as the cause of type I hyperlipoproteinemia in several patients.Two unrelated patients were referred to our Lipid Units because of a severe hypertriglyceridemia and recurrent pancreatitis. We measured LPL activity in postheparin plasma and serum ApoCII and sequenced LPL, APOC2, and GPIHBP1.The 2 patients exhibited very low LPL activity not associated with mutations in LPL gene or with ApoCII deficiency. The sequence of GPIHBP1 revealed 2 novel point mutations. One patient (proband 1) was found to be homozygous for a CA transversion in exon 3 resulting in the conversion of threonine to lysine at position 80 (p.Thr80Lys). The other patient (proband 2) was found to be homozygous for a GT transversion in the third base of the ATG translation initiation codon in exon 1, resulting in the conversion of methionine to isoleucine (p.Met1Ile).In conclusion, we have identified 2 novel GPIHBP1 missense mutations in 2 unrelated patients as the cause of their severe hypertriglyceridemia.

The long-term behavioral consequences of acute immobilization (IMMO) in rats and the effects of 5-HT(1A) receptor activation (8-OH-DPAT: 0.3 mg/kg, sc) were studied. Corticosterone levels after IMMO with previous 8-OH-DPAT treatment were also studied. Twenty-four hours after IMMO (3 h), rats performed conditioned (passive avoidance) and unconditioned (escape behavior) anxiety tests in the elevated T maze. Pre-exposure to IMMO induces long-term behavioral changes in contrast with control rats. These behavioral alterations include an increase of anxiogenic responses, such as exploratory behavior and passive avoidance response. This effect was counteracted by 8-OH-DPAT pretreatment and reversed by WAY-100635 when administered before 8-OH-DPAT. Serum corticosterone levels increased during the first hour of stress and after 8-OH-DPAT administration. Our results support the hypothesis that involvement of acute stress is crucial in the anxiety-like behaviors and in the potentiation of fear. The activation of 5-HT(1A) receptors counteracted the long-term effects induced by IMMO.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an emerging risk factor for cognitive impairment. Whether this impairment is a direct effect of this metabolic disorder on brain function, a consequence of vascular disease, or both, remains unknown. Structural and functional neuroimaging studies in patients with T2DM could help to elucidate this question. OBJECTIVE: We designed a cross-sectional study comparing 25 T2DM patients with 25 age- and gender-matched healthy control participants. Clinical information, APOE genotype, lipid and glucose analysis, structural cerebral magnetic resonance imaging including voxel-based morphometry, and F-18 fluorodeoxyglucose positron emission tomography were obtained in all subjects. METHODS: Gray matter densities and metabolic differences between groups were analyzed using statistical parametric mapping. In addition to comparing the neuroimaging profiles of both groups, we correlated neuroimaging findings with HbA1c levels, duration of T2DM, and insulin resistance measurement (HOMA-IR) in the diabetic patients group. RESULTS: Patients with T2DM presented reduced gray matter densities and reduced cerebral glucose metabolism in several fronto-temporal brain regions after controlling for various vascular risk factors. Furthermore, within the T2DM group, longer disease duration, and higher HbA1c levels and HOMA-IR were associated with lower gray matter density and reduced cerebral glucose metabolism in fronto-temporal regions. CONCLUSION: In agreement with previous reports, our findings indicate that T2DM leads to structural and metabolic abnormalities in fronto-temporal areas. Furthermore, they suggest that these abnormalities are not entirely explained by the role of T2DM as a cardiovascular risk factor. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

To determine lipid serum levels, lipoproteins and other markers related to nephropathy and peripheral arterial disease (PAD) in a type 2 diabetes population stratified according to their level of renal dysfunction.A cross-sectional study was conducted on 72 type 2 diabetic patients followed-up in outpatient clinics. Patients were divided into 4 groups according to their estimated glomerular filtration rate (eGFR, mL/min) and albumin/creatinine ratio (ACR, mg/g) (eGFR60 and ACR30 [n = 23], eGFR60 and ACR30 [n = 12], eGFR30-60 [n = 23] and eGFR30 [n = 14]). Clinical and anthropometric characteristic of all patients were recorded. Fasting lipids and apolipoproteins, as well as renal and hematology parameters were measured. Finally, a multivariate Wald stepwise logistic regression statistic analysis was performed to determine variables independently associated with the presence of renal dysfunction.The univariate statistical analysis showed that the higher renal dysfunction, the higher the prevalence of hypertension, smoking habit and triglycerides levels, and the lower hemoglobin levels (P.05). The multivariate statistical analysis showed that only triglycerides levels (OR: 1.019, 95% CI: 1.004-1.034) and hemoglobin levels (OR: 0.516 95% CI: 0.292-0.914) were independently associated to the presence of renal dysfunction (eGFR60 mL/min.). The further inclusion of the presence of PAD in the statistical model did not modify those associations.The results confirm the relationship between triglycerides levels and diabetic nephropathy, independently of the presence of PAD.

An earlier study showed that fasting and postprandial concentrations of apolipoprotein B48 were raised in patients with type 2 diabetes (DM2) and peripheral arterial disease (PAD) as compared with persons without DM2 or persons with DM2 but not PAD. The aim of this study was to confirm the association of PAD and B48 in a larger group of patients with DM2 and the relation of B48 with the preheparin lipoprotein lipase (LPL) mass. We studied 456 patients with DM2. PAD was defined as an ankle-brachial index (ABI)0.9. Apolipoprotein B48 was quantified by ELISA. Apo B48 was significantly higher in the group with an ABI0.9 than the groups with ABI of 0.9-1.3 and1.3 (10.7 ± 6.28 vs. 9.24 ± 5.5 vs. 9.17 ± 8.8 mg/L, ANOVA test, p0.05). B48 was independently associated with an ABI0.9 (OR 1.053; 95 % CI, 1.013-1.094; p0.05), together with smoking and duration of diabetes. The preheparin LPL mass was similar in the patients with and without PAD. In conclusion, we confirmed that fasting B48 is an independent marker of PAD in patients with DM2, unrelated to the preheparin LPL mass, statin therapy or glucose lowering treatment.

Backgorund Mixed hyperlipidemia is common in patients with diabetes. Statins, the choice drugs, are effective at reducing lipoproteins that contain apolipoprotein B100, but they fail to exert good control over intestinal lipoproteins, which have an atherogenic potential. We describe the effect of prescription omega 3 fatty acids on the intestinal lipoproteins in patients with type 2 diabetes who were already receiving fluvastatin 80 mg per day. Methods Patients with type 2 diabetes and mixed hyperlipidemia were recruited. Fasting lipid profile was taken when patients were treated with diet, diet plus 80 mg of fluvastatin and diet plus fluvastatin 80 mg and 4 g of prescription omega 3 fatty acids. The intestinal lipoproteins were quantified by the fasting concentration of apolipoprotein B48 using a commercial ELISA. Results The addition of 4 g of prescription omega 3 was followed by significant reductions in the levels of triglycerides, VLDL triglycerides and the triglyceride/HDL cholesterol ratio, and an increase in HDL cholesterol (P < 0.05). Fluvastatin induced a reduction of 26% in B100 (P < 0.05) and 14% in B48 (NS). However, the addition of omega 3 fatty acids enhanced this reduction to 32% in B100 (NS) and up to 36% in B48 (P < 0.05). Conclusion Our preliminary findings therefore suggest an additional benefit on postprandial atherogenic particles when omega 3 fatty acids are added to standard treatment with fluvastatin.

Serum IGF-I levels decline with age. We have recently reported that in aging rats the exogenous administration of IGF-I restores IGF-I circulating levels and age related-changes, improving glucose and lipid metabolisms, increasing testosterone levels and serum total antioxidant capability, and reducing oxidative damage in the brain and liver associated with a normalization of antioxidant enzyme activities. Understanding that mitochondria are one of the most important cellular targets of IGF-I, the aims of this study were to characterize mitochondrial dysfunction and study the effect of IGF-I therapy on mitochondria, leading to cellular protection in the following experimental groups: young controls, untreated old rats, and aging rats treated with IGF-I. Compared with young controls, untreated aging rats showed an increase of oxidative damage in isolated mitochondria with a mitochondrial dysfunction characterized by: depletion of membrane potential with increased proton leak rates and intramitochondrial free radical production, and a significant reduction of ATPase and complex IV activities. In addition, mitochondrial respiration from untreated aging rats was atractyloside insensitive, suggesting that the adenine nucleotide translocator was uncoupled. The adenine nucleotide translocator has been shown to be one of the most sensitive locations for pore opening. Accordingly, untreated aging rats showed a significant overexpression of the active fragment of caspases 3 and 9. IGF-I therapy corrected these parameters of mitochondrial dysfunction and reduced caspase activation. In conclusion, these results show that the cytoprotective effect of IGF-I is closely related to a mitochondrial protection, leading to reduce free radical production, oxidative damage, and apoptosis, and to increased ATP production.

The aim of our study was to evaluate the effect of acute stress and the 5-HT1A receptor involvement in both, the hippocampus noradrenaline (NA) tissue levels and the c-Fos immunoreactivity (c-Fos-IR) in the catecholaminergic neurons of the locus coeruleus (LC). Double immunocytochemical staining of tyrosine hydroxilase (TH) and c-Fos protein combined with stereological techniques were used to study the specific cell activation in the LC neurons in five experimental groups (control group, immobilization (1 h) group, 8-OH-DPAT group (8-OH-DPAT 0.3 mg/kg, s.c.), DPAT + IMMO group (8-OH-DPAT 0.3 mg/kg, s.c., 30′ prior acute immobilization) and WAY + DPAT + IMMO group (WAY-100635 0.3 mg/kg, s.c. and 8-OH-DPAT 0.3 mg/kg, s.c., 45′and 30′, respectively, before immobilization). The results showed that hippocampal NA tissue levels and c-Fos-IR in the TH positive neurons of the LC were significantly increased immediately and after 90′, respectively, after the immobilization period. Pre-treatment with 8-OH-DPAT counteracted the effects induced by immobilization, but pre-treatment with WAY-100635 did not block the effects induced by 8-OH-DPAT. These results suggest that noradrenaline system is associated in a significant way with immobilization stress. The role of 5-HT1A receptor activation in this stress response is also discussed.

Aims To determine whether postprandial lipid levels are markers of clinical and subclinical macrovascular disease in a select group of patients with type 2 diabetes. Methods We recruited 119 local patients with type 2 diabetes and moderate metabolic control (HbA1c

The serotoninergic system and the 5-HT1A receptors have been involved in the brain response to acute stress. The aim of our study was evaluate the role of the 5-HT1A receptors in serotoninergic cells of rostral and caudal raphe nuclei under acute immobilization in rats. Double immunocytochemical staining of 5-hydroxy-tryptamine and c-Fos protein and stereology techniques were used to study the specific cell activation in the raphe nuclei neurons in five groups (control group, immobilization group (immobilization lasting 1 h), DPAT group (8-OH-DPAT 0.3 mg/kg, s.c.), DPAT + IMMO group (8-OH-DPAT 0.3 mg/kg, s.c., 30 � prior acute immobilization) and WAY + DPAT + IMMO group (WAY-100635 0.3 mg/kg, s.c. and 8-OH-DPAT 0.3 mg/kg, s.c., 45 � and 30 � , respectively, before immobilization). Our results showed an increase in the number of c-Fos immunoreactive nuclei in serotoninergic cells in both dorsal and median raphe nuclei in the immobilized group. The 8-OH-DPAT pretreatment counteracted the excitatory effects of the acute immobilization in these brain regions. In addition, WAY-100635 administration reduced the effect of 8-OH-DPAT injection, suggesting a selective 5-HT1A receptor role. Raphe pallidus and raphe obscurus did not show any differences among experimental groups. We suggest that somatodendritic 5-HT1A receptors in rostral raphe nuclei may play a crucial role in both mediating the consequences of uncontrollable stress and the possible beneficial effects of treatment with 5-HT1A receptor agonists. © 2005 Elsevier Ireland Ltd. All rights reserved.